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2011 Revista Nefrologa. rgano Oficial de la Sociedad Espaola de Nefrologa

revisiones cort as

Obesity and chronic kidney disease


G. Eknoyan
Renal Section, Department of M edicine. Baylor College of M edicine. Houston, Texas (USA)

Nefrologia 2011;31(4):397-403
doi:10.3265/Nefrologia.pre2011.M ay.10963

ABSTRACT

Obesidad y enfermedad renal crnica


RESUM EN

Obesit y is associat ed w it h t he early onset of


glomerulomegaly,
hemodynamic changes of
a
hyperf ilt ering kidney, and increased albuminuria, w hich
are pot ent ially reversible w it h w eight loss. How ever,
pat hologic lesions of f ocal segment al glomerulosclerosis
develop in experiment al models of sust ained obesit y, and
are observed in morbidly obese humans present ing w it h
massive prot einuria. In addit ion, several observat ional,
cross sect ional and longit udinal st udies document t hat
obesit y is as an independent risk f act or f or t he onset ,
aggravat ed course, and poor out comes of chronic kidney
disease, even af t er adjust ment f or conf ounding comorbidit ies including met abolic syndrome, diabet es and
hypert ension, t he major causes of chronic kidney disease.
Early diet ary int ervent ion t o reduce w eight , and w here
necessary bariat ric surgery, should be considered in t he
management of overw eight and obese chronic kidney
disease (CKD) pat ient s.
Keyw ords: Obesity. Kidney disease. Diabetes. Albuminuria.
Hypertension.

La obesidad est relacionada con la aparicin t emprana


de glomerulomegalia, las alt eraciones hemodinmicas
del rin hiperf ilt rant e y el aument o de la albuminuria,
snt omas que son reversibles con una prdida de peso.
Por el cont rario, las lesiones pat olgicas de la glomeruloesclerosis f ocal y segment aria se desarrollan en modelos experiment ales de obesidad mant enida y se observan
en pacient es con obesidad mrbida que present an prot einuria masiva. Adems, dif erent es est udios observacionales, t ransversales y longit udinales han demost rado
que la obesidad supone un f act or de riesgo independient e de la aparicin, el empeoramient o, y la escasa respuest a al t rat amient o de la enf ermedad renal crnica (ERC),
incluso despus de ajust ar por variables de conf usin, incluido el sndrome met ablico, la diabet es y la hipert ensin, las principales causas de la enf ermedad renal crnica. En los pacient es con enf ermedad renal crnica que
present an sobrepeso y obesidad debe considerarse la inst auracin precoz de una diet a para reducir peso y la ciruga barit rica, en caso de ser necesaria.
Palabras clave: Obesidad. Enf ermedad renal. Diabet es.
Albuminuria. Hipertensin.

INTRODUCTION

Throughout most of human history corpulence has been


considered a sign of good health and being fat an advantage.
The potential of harmful effects of excess body weight were
appreciated in the 19th century, but it is only in the early
decades of the 20th century that the complications and
increased morbidity and mortality of obesity began to be
documented1. Since then, the accrued evidence clearly
indicates that fat cells provide not merely energy storage but
that components of excess adipose tissue function as an
Correspondence: Garabed Eknoyan
Renal Section. Department of M edicine.
Baylor College of M edicine. One Baylor Plaza,
TX 77030, Houston. Texas. USA.
geknoyan@bcm.edu

endocrine organ with multiple detrimental health


consequences, and that obesity frequently contributes to the
pathogenesis, complicates the course, and increases the risk of
several diseases including diabetes, hypertension,
cardiovascular disease, metabolic syndrome, certain
malignancies, and kidney disease (Table 1)2,3. The importance
and urgency of identifying the detrimental consequences of
obesity has been the dramatic increase in its incidence and
prevalence after the Second World War. Population surveys
indicate that two thirds of United States adults are
overweight and one third obese4,5. Similar trends documented
in other parts of the world have led to the identification of
obesity as a worldwide public health problem of epidemic
proportions with increasing incidence, high costs, and poor
outcomes1-6.
397

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G. Eknoyan. Obesit y and CKD

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Table 1. Co-morbidit ies associat ed w it h overw eight
and obesit y
1. Diabetes
2. Hypertension
3. M etabolic syndrome
4. Cardiovascular disease
5. Cancer
6. Osteoarthritis
7. Gall bladder disease
8. Non-alcoholic liver disease
9. Pancreatitis
10. Obstructive sleep apnea
11. Depression
12. Chronic kidney disease

The first renal complication to be associated with obesity was


renal cell carcinoma7. The effects of obesity on kidney function
and disease have since been identified and become a subject of
increased study and concern8-12. Actually, an effect of obesity on
albuminuria and blood pressure in kidney disease was reported
as early as 192313, when actuarial data first began to identify
overweight as a risk factor for mortality, but were forgotten or
neglected when cardiovascular mortality emerged as the
principal cause of obesity-related mortality1. Based on a metaanalysis, it has been estimated that the presence of kidney
disease is related to overweight (BMI = 25-29.9) and obesity
(BMI _>30)14. An association between obesity and kidney disease
could be made in 24.2% of males and 33.9% of females in the
U.S., and in industrialized countries in 13.8% of men and
24.9% of women. Furthermore, obesity was shown to adversely
affect the progressive loss of kidney function among those with
chronic kidney disease (CKD)14. Regrettably, the detrimental
renal effects of obesity remain unrecognized and are not
included in major reviews of obesity3.
This article reports the effects of obesity on the normal and
diseased kidney (Table 2), considers the factors implicated in their
pathogenesis, and presents an approach to their management.

Cross sectional and longitudinal clinical studies confirm these


hemodynamic changes characteristic of a hyperfiltering
glomerulus in humans, whose first clinical manifestation of
renal injury appears to be increased albuminuria18,19.
Compared to lean subjects, in severely obese individuals the
GFR and renal plasma flow were shown to be higher by 51
and 31 percent, respectively20. Glomerular macromolecular
sieving studies in these individuals indicate that a principal
reason for these hemodynamic effects and attendant increase
in glomerular filtration fraction is due to afferent arteriolar
dilatation. An added contributory role of efferent arteriolar
vasoconstriction on the increased filtration fraction, due to
stimulation of the renin-angiotensin system, has been
documented also and is supported by the salutary effect of
angiotensin receptor blocking drugs on the albuminuria and
renal hemodynamics in experimental and clinical studies of
obesity21,22. Evidence also exists for a role of obesity-induced
increase in renal sympathetic tone that could contribute and
aggravate these hemodynamic changes23,24.
A significant correlation between increased urinary albumin
excretion and body weight has been shown in both nondiabetic and diabetic overweight individuals19,25-27. The effect
of obesity on proteinuria is not bimodal, but a continuum
that is directly related to increasing body mass index (BMI).
In a retrospective analysis of the database of a population

Table 2. Eff ect s of overw eight and obesit y on t he kidney


Hemodynamic

 Effective plasma flow


 Glomerular filtration rate
 Glomerular filtration fraction
 Albuminuria
Structural
 Kidney w eight
 Glomerular planar surface
M esangial expansion
Podocyte injury

Pathologic
Glomerulomegaly
Glomerulosclerosis
Obesity related glomerulopathy

EFFECTS OF OBESITY ON RENAL HEM ODYNAM ICS

Experimental studies in genetically obese rats and force fed dogs


show an early onset of hemodynamic changes in kidney function
characterized by an increase in glomerular filtration rate (GFR)
and effective plasma blood flow, accompanied by variable
increments in filtration fraction and albumin excretion15,16. These
early changes are reversible as shown in studies of hyperphagic
obese Zucker rats in which, early (at 6 or 12 weeks of age) but
not late (after 26 weeks of age), food restriction was associated
with reversal of glomerular hyperfiltration and albuminuria17.
398

Chronic kidney disease

 Onset of kidney disease


 Progression to kidney failure
 Proteinuria
End-stage renal disease
 Incidence and prevalence
Survival advantage in hemodialysis

 Graft loss in kidney transplant recipients


Other
 Renal cell carcinoma
 Nephrolithiasis
Nefrologia 2011;31(4):397-403

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study on the impact of microalbuminuria on renal and


cardiovascular risk, the prevalence of microalbuminuria (30300 mg/d) in men increased from 9.5% in those with normal
body weight (BMI <25) to 18.3% in those who were overweight, and to 29.3% in those who were obese; in women,
the respective percentages were 6.6%, 9.2%, and 16.0%26.

retrospective analysis of kidney biopsies at one center that


revealed a 10-fold increase in its occurrence over the 15 year
period of the study36. The occurrence of glomerulosclerosis
only in selected cases of obesity may be related to genetic
predisposition, the presence of other co-existent risk factors,
and the severity and duration of obesity.

The hemodynamic effects of overweight on kidney function and


albuminuria are magnified in the presence of hypertension, which
itself is a clinical complication of obesity10,19,28. A similar amplifier
effect of obesity has been reported in overweight diabetics27. In a
cross-sectional study of risk factors for microalbuminuria among
African Americans with newly diagnosed type 2 diabetes, 23.4%
of whom had microalbuminuria, the urine albumin to creatinine
ratio was independently associated with BMI27. Importantly,
moderate weight reduction (4.1%) in overweight diabetics who
were proteinuric decreased their proteinuria by about 30%29. There
is now convincing evidence of a salutary effect of weight
reduction, by bariatric surgery or dietary caloric restriction, on the
proteinuria of obese individuals30,31.

Clinically, obesity-related glomerulopathy is associated with


proteinuria and was first described in 1974 in four morbidly
obese patients (BMI >50 kg/m2) who presented with
nephrotic syndrome, none of whom were diabetic and only
two were hypertensive37. Kidney biopsies on two of them
revealed focal and segmental glomerulosclerosis. In all four
cases the proteinuria decreased during dietary-induced
weight loss. Nephrotic range proteinuria has been reported
also in severe obesity with normal kidney biopsy38.
Reduction of nephrotic range proteinuria in obese diabetics
occurs with weight loss after gastric bypass surgery39,40. In
morbidly obese individuals who develop non-nephrotic
range albuminuria, the histologic changes appear to precede
the onset of microalbuminuria, and the onset of proteinuria
precedes the decline in GFR by several years41.

In evaluating kidney function in obese individuals, it is


important to note that currently available methods of
estimated GFR (eGFR) were derived in lean individuals; both
the Cockcroft-Gault formula and the MDRD equation are less
accurate in malnourished as well as obese individuals. The
Cockcroft-Gault formula grossly overestimates eGFR and
should not be used in obese individuals. The MDRD equation
appears to be more dependable in obesity, but also tends to err
by 10 ml/min/1.73 m2 or more in obese cases32,33.

EFFECTS OF OBESITY ON RENAL M ORPHOLOGY


AND PATHOLOGY

In force-fed dog studies, the hemodynamic changes of obesity


were associated with an increase in kidney weight of about
40%10,15. This was accompanied by an increase of glomerular
size together with podocyte injury and expansion of the
mesangium, and in sustained obesity resulted in mesangial
sclerosis15. As with the hemodynamic changes, these early
structural changes of obesity were prevented by dietary
restriction in hyperphagic Zucker rats16.
In humans, despite the occurrence of glomerulomegaly,
hyperfiltration, and albuminuria most obese individuals do not
develop glomerulosclerosis34. In a study comparing kidney
biopsies from obese to lean living kidney donors the glomerular
planar surface area was significantly greater in those who were
obese but showed no evidence of glomerulosclerosis18.
However, cases of glomerulomegaly, focal segmental
glomerulosclerosis, proteinuria, and decreased kidney function
do occur in obesity, a clinicopathothological entity that has
been termed obesity-related glomerulopathy35. The increased
prevalence of obesity appears to be reflected in an increased
incidence of obesity-related glomerulopathy, as shown in a
Nefrologia 2011;31(4):397-403

The long term prognosis of obesity-related glomerulopathy


is poor, but unlike idiopathic focal segmental sclerosis,
in obesity-related glomerulopathy the incidence of nephrotic
range proteinuria is lower, the serum albumin higher,
the serum cholesterol lower, the edema less severe, and the
progression to end-stage renal disease slower34,42.

EFFECT OF OBESITY ON PROGRESSION


OF KIDNEY DISEASE

In population based epidemiologic studies, obesity has been


shown to be associated with new onset of CKD and increased
rate of progression to kidney failure in individuals with
existing primary kidney disease8-12. In a study of predictors of
new onset kidney disease, in a cohort of 2585 patients
followed for 20 years, the odds ratio for new onset of
chronic kidney disease was 1.23 per one standard increase in
BMI43. Increased BMI has also been shown to increase the
risk of progression of existing kidney disease, adjusted for
confounders including diabetes and hypertension. Obese
individuals with CKD have a higher rate of decline in
glomerular filtration rate and progress faster to end-stage
renal disease (ESRD)44. In a large population study
evaluating the risk for ESRD over a span of 20 years,
increased BMI was an independent risk factor for
progression to ESRD in obese individuals compared to those
with normal body weight45. In another population-based case
controlled study, a BMI of over 25 at age 20 was associated
with a threefold increased risk for developing new onset of
kidney disease, even after correction for hypertension and
diabetes46. The coexistence of diabetes and obesity in this
study doubled the risk for new onset of kidney disease.
399

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Direct evidence for a detrimental effect of obesity on kidney
disease comes from the study of specific diseases such as IgA
nephritis, where excessive body weight (BMI >
_25) at the time
of kidney biopsy was shown to be associated with the
severity of the detected pathologic lesions, the subsequent rate
of loss of kidney function, and to be an independent risk
factor for progression to ESRD41,47. Similar results have been
observed on the onset of proteinuria and progressive loss of
kidney function after unilateral nephrectomy in obese
individuals48. At the 20-year follow up of this study, most of
the normal non-obese individuals had normal kidney
function as compared to only about 40% of the expected
GFR for age in the obese subjects. These observations are
more dramatically evident in kidney transplant recipients. In
an analysis of a large registry database (51927 kidney
transplant recipients), it was shown that the relative risk of
graft loss, patient death, and cardiovascular mortality
increased49 by 20-40% at increasing BMIs of over 30 kg/m2.
As a result, a BMI of over 35 kg/m2 has come to be considered
a contraindication to kidney transplantation in some centers.
The detrimental effect of overweight on the course of CKD is
supported by several epidemiologic studies that show a higher
prevalence and increasing incidence of obesity in patients with
ESRD being initiated on dialysis50. In a study of over 300,000
subjects, the presence of obesity was shown to increase the
relative risk of ESRD, adjusted for confounding factors45. Once
again, this relationship was not related to obesity bi-modally,
but showed an incremental continuum related to increased BMI
that was statistically significant at BMI values of >25.
Compared to lean subjects, the relative risk of ESRD was 3.57
for those with a BMI of 30-34.9, 6.12 for those with a BMI of
35-39.9, and 7.07 for those with morbid obesity (BMI >40)45.

EFFECT OF OBESITY IN CHRONIC AND ACUTE


DIALYSIS PATIENTS

Contrary to the convincing evidence of a detrimental effect of


obesity on the onset, course, and outcomes of CKD, obesity in
dialysis patients appears to provide a survival advantage, an
effect that has been dubbed reverse epidemiology51. This
striking disparity with the usual detrimental effects of obesity on
survival in CKD may be due to the relatively higher mortality
of chronic kidney disease patients during the progression of
their disease with only those having inherent survival
advantages progressing to ESRD, and the fact that the initial
reported analysis compared variable survival data (10 years for
normal, 4 years in dialyzed patients). In a study in which
subjects were followed for a comparable period, obesity was
shown actually to increase mortality in dialysis patients52.
Another reason for an advantage of obesity in dialyzed
patients may be teleological. The genetic origins of obesity
rooted in the survival advantage it provided at times of
famine may be operative in ESRD patients on dialysis.
400

G. Eknoyan. Obesit y and CKD

Maintenance hemodialysis is essentially a catabolic state


similar to malnutrition in which obesity may convey some
survival advantage to dialysis patients, much like it did to
their ancestral hunters-gatherers at times of food scarcity1,53.
The survival advantage proffered by obesity is not limited to
dialyzed patients but is also observed in other chronic
diseases such as congestive heart failure, liver cirrhosis, and
obstructive pulmonary disease3,6,54.
Relevant to this issue is the finding that obesity also confers
survival advantage in intensive care unit (ICU) patients
requiring renal replacement therapy54. As in the case of
CKD, obesity was an independent risk factor for developing
acute kidney injury in the ICU, but conveyed improved
survival in those requiring dialysis.

OTHER EFFECTS OF OBESITY ON THE KIDNEY

Obesity is associated with an increased risk for renal cell


carcinoma7. Past cautiousness in considering this as the only
renal complication of obesity likely reflects the fact that the
renal complications of obesity were initially attributed to be
secondary to the common association of obesity with
hypertension and diabetes, the two most common causes of
chronic kidney disease6. An improper caution refuted by the
data reviewed here, but an error that regrettably continues to
be perpetuated in the current literature3.
Actually, the relationships between obesity, hypertension,
diabetes, cardiovascular disease, metabolic syndrome and
CKD can be viewed as the clinical intersection of a cluster of
diseases that are associated with kidney disease (Figure 1).
The coexistence of obesity in any of these diseases (diabetes,
hypertension, metabolic syndrome, cardiovascular disease)
magnifies the risk of onset of kidney disease and its
progression to ESRD. Conversely, the coexistence of obesity
and chronic kidney disease in any of those other diseases
increases their risk of morbidity and mortality6.

OBESITY, DIABETES, AND THE KIDNEY

Whereas thermodynamic studies clearly establish fat


deposition as a consequence of imbalance between the
energy derived from ingested food and that of energy
expended in the course of daily activities, obesity is in fact a
multifactorial disease in which the adipose tissue rather than
just being a site for excess energy storage actually functions
as an endocrine and exocrine organ with neurohumoral and
vasoactive effects that are implicated in the genesis of
obesity-related organ damage including the kidney (Table 3).
In addition to angiotensinogen and renin, adipose tissue
produces several cytokines, growth factors, and bioactive
adepokines that have been implicated in or associated with
kidney injury13,53-63.
Nefrologia 2011;31(4):397-403

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Table 3. Fact ors implicat ed in t he pat hogenesis
of CKD in obesit y
 Renin angiotensin system
 Aldosterone
 Sympathetic nervous system
 Insulin resistance
 Salt intake
Altered adepokines

 Leptin
 Fetuin-A
Resistin
 Adenopectin
 Tumor necrosis factor-
 Free fatty acids
M S: metabolic syndrome; HBP: high blood pressure; DM : diabetes
mellitus; CVD: cardiovascular disease; CKD: chronic kidney disease.

Figure 1. The clust er of co-morbidit ies associat ed w it h and


aggravat ed by obesit y. W here t here is clinical int ersect ion of
a given circle w it h t hat of obesit y, t he co-exist ence of
obesit y emerges as a risk mult iplier of t he out comes of t hat
disorder. The areas w here t here is an overlap of more t han
one circle t he risks are f urt her magnif ied.

Among the commonly implicated mechanisms of organ


damage is that of insulin resistance that characterizes the
obese and type II diabetics 58, and may account for the
hemodynamic disorders of obesity-related hyperfiltration,
glomerulomegaly, and albuminuria that are also the
characteristics of early diabetic nephropathy. Although an
association between microalbuminuria and BMI is a
feature of non-diabetic obese subjects, in clinical studies
of diabetics it is rather difficult to separate the effects of
increased BMI alone from its concomitant effects on
glycemic control 27. However, the lesions of obesityrelated glomerulopathy are distinctly different from those
of diabetic nephropathy6. The characteristic lesions of
nodular sclerosis and membranous thickening of diabetic
nephropathy are not observed in the classic lesions of
obesity-related glomerulopathy, which is one of focal
segmental glomerlosclerosis. In a study comparing the
kidney biopsies of microalbuminuric diabetic subjects,
there was no difference in glomerular pathology of obese
compared to lean diabetics who were biopsied64. The
severe hyperglycemia and advance glycated end products
(AGE) in diabetes have been incriminated for these
structural differences, but remain to be proven. Thus,
whereas obesity per se results in distinct hemodynamic,
structural, and pathologic changes in the kidney, in addition
it is an independent amplifier of the risk associated with
CKD in general and with diabetic nephropathy, in
particular (Figure 1).
Nefrologia 2011;31(4):397-403

 Endothelin-1
 Brain natriuretic protein
 Plasminogen activator inhibitor-1
Infiltrating macrophage phenotypic sw itch

By the same token, whereas the lesions of obesity-related


glomerulopathy are similar to those of idiopathic focal
segmental glomerulonephritis, there are clinical differences
apart from the glomerulomegaly of obesity that distinguishes
them from each other6,34. Viewed in an evolutionary
framework, the millennia of human evolution during which
the genetic advantages of obesity changed it from one of
survival advantage to a disease after food became easily
available, was accompanied by the evolution of genetically
diverse populations, who are divergent in their genetic
susceptibility to the consequences of diseases in general and
of obesity-related renal disease in particular. This may
account, at least in part, why the renal morphologic
complications of obesity are encountered clinically in some
but not all obese individuals, whereas its detrimental
hemodynamic effects are variably expressed, in most of
those with primary forms of CKD, including diabetic
nephropathy. Coupled with environmental factors and other
acquired life style changes (smoking, exercise, type of food)
this may account for the variations in obesity-related
complications in general and that of obesity-related
glomerulosclerosis in particular. Obviously, there remain
many gaps in our current knowledge of these effects that
remain to be explored and explained.

CONCLUSION

In summary, a growing body of evidence that is convincing


in balance indicates specific hemodynamic, structural, and
functional changes of the kidney in obesity, and the onset of
obesity-related glomerulosclerosis in some of them. In
401

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G. Eknoyan. Obesit y and CKD

revisiones cort as
addition, the presence of obesity amplifies the risk for and
outcomes of chronic kidney disease in diabetes,
hypertension, metabolic syndrome, primary kidney diseases,
and cardiovascular disease (Figure 1). Given the evidence
for the potential reversibility of these detrimental obesityrelated hemodynamic effects and the proteinuria of obesity
on progression of kidney diseases and their outcomes,
weight reduction (dietary or bariatric surgery) should be
considered a component of the therapeutic regimen of all
overweight individuals with CKD30,31.

14. Wang Y, Chen X, Song Y, Caballero B, Cheskin LJ. Associat ion


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Apart from caloric restriction, given the tendency to salt


retention of obesity salt restriction must be part of their
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consideration should be given to the use of bicarbonate
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Enviado a Revisar: 10 M ay. 2011 | Aceptado el: 10 M ay. 2011


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